Kaempferol induces cell death through ERK and Akt-dependent down-regulation of XIAP and survivin in human glioma cells.
The present study was undertaken to determine the molecular mechanism by which kaempferol induces cell death in human glioma cells. Kaempferol resulted in loss of cell viability and inhibition of proliferation in a dose- and time-dependent manner, which were largely attributed to cell death. Kaempferol caused an increase in reactive oxygen species (ROS) generation and the kaempferol-induced cell death was prevented by antioxidants, suggesting that ROS generation is involved in kaempferol-induced cell death. Kaempferol caused depolarization of mitochondrial membrane potential. Western blot analysis showed that kaempferol treatment caused a rapid reduction in phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. The ERK inhibitor U0126 and the Akt inhibitor LY984002 increased the kaempferol-induced cell death and overexpression of MEK, the upstream kinase of ERK, and Akt prevented the cell death. The expression of anti-apoptotic proteins XIAP and survivin was down-regulated by kaempferol and its effect was prevented by overexpression of MEK and Akt. Kaempferol induced activation of caspase-3 and kaempferol-induced cell death was prevented by caspase inhibitors. Taken together, these findings suggest that kaempferol results in human glioma cell death through caspase-dependent mechanisms involving down-regulation of XIAP and survivin regulating by ERK and Akt.
Jeong
Ji Cheon
JC
Department of Oriental Medicine, Dongguk University, Kyung Ju, South Korea.
Kim
Min Soo
MS
Kim
Thae Hyun
TH
Kim
Yong Keun
YK
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001932:Brain Neoplasms; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D016923:Cell Death; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005910:Glioma; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D044949:Kaempferols / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis*
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D051034:Inhibitor of Apoptosis Proteins; D044949:Kaempferols; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C006552:kaempferol; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3